Genes which are important in cancer predisposition in the general population may be identified because they cause in homozygous individuals a distinctive autosomal recessive syndrome. The best evidence for this hypothesis has come from our studies of cancer incidence in families of probands with cancer-associated autosomal recessive syndromes. By comparing the observed number of cancers or cancer deaths, both total and at specific sites, to that expected if the set of families were a random sample of the general population, it is possible to determine which cancers are associated with specific genes and to measure the relative risk of that cancer for heterozygous carriers. Spouse controls are used and epidemiological parameters are evaluated to be as certain as possible that detected associations are related to the gene under study. We are completing studies of 26 families with common variable immunodeficiency and 28 families with combined immunodeficiency. Preliminary analysis indicates that heterozygous carriers of genes for these conditions will have important cancer predisposition. An earlier study of 27 ataxia-telangiectasia (AT) families revealed substantial cancer predisposition for AT heterozygotes but left unresolved in some instances the question of which cancers. In addition, those AT family data suggested that the AT heterozygote might be predisposed to diabetes mellitus or specific birth defects. These questions are important because of evidence that AT heterozygotes comprise 1 percent or more of the population. We propose now a population-based study of 100 AT families which resolve these questions through a retrospective and prospective study of a sufficiently large sample of obligatory heterozygotes and close relatives.